Colon targeting can be very helpful for many pharmaco-therapies, including the treatment of inflammatory bowel diseases, such as Crohn's Disease (CD) and Ulcerative Colitis (UC).
If a locally acting drug is orally administered using a conventional pharmaceutical dosage form, the latter rapidly dissolves in the contents of the stomach, the drug is released and likely to be absorbed into the blood stream. This leads to elevated systemic drug concentrations and, thus, an increased risk of undesired side effects and at the same time to low drug concentrations at the site of action in the colon, resulting in poor therapeutic efficiency. These restrictions can be overcome if drug release is suppressed in the stomach and small intestine and time-controlled in the colon. This type of site-specific drug delivery to the colon might also offer an interesting opportunity for protein and peptide drugs to get absorbed into the systemic circulation upon oral administration.
To allow for colon targeting, the drug can for instance be embedded within a polymeric matrix former, or drug-loaded tablets or pellets such as spherical beads, approximately 0.5-1 mm in diameter; can be coated with a polymeric film. In the upper gastro intestinal tract (GIT), the permeability of the polymeric networks for the drug should be low, whereas the macromolecular barriers must become permeable once the colon is reached. This increase in drug permeability of the polymeric networks at the site of action might be induced by: (i) a change in the pH of the contents of the GIT, (ii) a change in the quality and/or quantity of enzymes along the GIT, or (iii) significant structural changes within the dosage form occurring after a pre-determined lag-time (e.g. crack formation in poorly permeable film coatings providing pulsatile drug release patterns). Alternatively, drug release might already start in the stomach and continue throughout the GIT, at a rate that is sufficiently low to assure that drug is still inside the dosage form once the colon is reached.
An attempt to solve the problem of colon targeting is disclosed in US2005220861A that relates to a controlled release formulation for delivery of prednisolone sodium metasulphobenzoate. The formulation comprises prednisolone sodium metasulphobenzoate surrounded by a coating comprising glassy amylose, ethyl cellulose and dibutyl sebacate, wherein the ratio of amylose to ethyl cellulose is from (1:3.5) to (1:4.5) and wherein the amylose is corn or maize amylose. In contrast to the American patent application number US2005220861, the system described in the present invention is adapted to the disease state of patients. This is a very crucial aspect, because to allow for colon targeting the dosage form must become more permeable for the drug once the colon is reached. This can for instance be assured by a preferential degradation of a compound that hinders rapid drug release in the upper gastro intestinal tract. This site-specific degradation can be based on significant differences in the quality and quantity of enzymes present in the upper gastro intestinal tract versus the colon. The compound should not be degraded in the upper gastro intestinal tract (and hinder drug release), but should be degraded in the colon (and, thus, allow for drug release). The performance of this type of advanced drug delivery systems is fundamentally depending on the environmental conditions in the colon of the patients, in particular on the types and concentrations of the enzymes present in the colon. It is well known and has been well documented in the literature that the disease state can significantly affect the quality and quantity of the enzyme secreting microflora in the gastro intestinal tract. This is particularly true for the microflora in the colon of patients suffering from inflammatory bowel diseases: the quality and quantity of the enzymes present in the colon of a patient can, thus, significantly vary from those in a healthy subject. Consequently, the performance of this type of drug delivery systems can significantly be affected by the disease state. Systems that are based on the preferential degradation by enzymes which are not present in sufficient concentrations in the disease state in the colon of the patient fail. The present invention reports for the first time on dosage forms allowing for controlled delivery of active ingredient under pathophysiological conditions: in feces of patients suffering from inflammatory bowel diseases. Thus, the performance of these dosage forms is assured under the given pathophysiological conditions in vivo. This is decisive for the success and safety of the treatment.
U.S. Pat. No. 6,534,549 relates to a method for producing a controlled release dosage form comprising a mixture of a substantially water-insoluble film-forming polymer and amylose in a solvent system comprising (1) water and (2) a water-miscible organic solvent which on its own is capable of dissolving the film-forming polymer is contacted with an active material and the resulting composition dried. The dosage form is particularly suitable for delivering therapeutic agents to the colon. In contrast to the present invention that disclosure addresses drug delivery systems prepared using an organic solvent. This is not the case in the present invention. The use of organic solvents implies several concerns, including toxicity and environmental concerns as well as explosion hazards. Furthermore, the use of amylose implies the extraction of this polymer and its stabilization. Amylose is extracted from starch after an hydrolysis and a purification step. This process is complex and difficulty usable at an industrial level. This formulation doesn't take into account the drug release kinetics for patients suffering from inflammatory bowel diseases. It has to be pointed out that the types and amounts of bacteria present in the colon of inflammatory bowel disease patients can significantly differ from those in healthy subjects. Thus, the types and amounts of enzymes secreted by these bacteria and being in contact with the drug delivery system can significantly differ. Consequently, the performance of the drug delivery system can significantly differ.